This invention relates to novel compositions of matter containing optically pure (+) doxazosin. These compositions are of utility in the treatment of patients with benign prostatic hyperplasia (BPH) or in the treatment of patients with elevated serum low density lipoprotein (LDL) levels. Pure (+) doxazosin exhibits little of the hypotensive activity associated with the (-) enantiomer and is therefore superior to racemic doxazosin for these indications. Also disclosed are methods for treating BPH and elevated LDL in a human while avoiding the hypotensive effects that are associated with the racemic mixture of doxazosin by administering the (+) isomer of doxazosin to said human.
The active compound of these compositions and methods is an optical isomer of doxazosin, which is described by Young and Brogden in Drugs 35, 525-541 (1988) and U.S. Pat. No. 4,188,390. Chemically, the active compound is the (+) isomer of 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-dimethoxyquin azoline also known as 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-1,4-benzodioxan-2 -yl)carbonyl]piperazine hereinafter referred to as doxazosin.
(+) Doxazosin, which is the subject of the present invention, is available commercially only as the 1:1 racemic mixture. That is, (+) doxazosin is available only as a mixture of optical isomers, called enantiomers. The racemic mixture of doxazosin is commercially available for administration as a methanesulfonate (mesylate) salt, but extensive pharmacology has been published on the hydrochloride salt as well.
Many organic compounds exist in optically active forms, i.e. they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. There is no correlation between nomenclature for the absolute stereochemistry and for the rotation of an enantiomer. Thus, D-lactic acid is the same as (-) lactic acid, and L-lactic acid is (+). For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
Doxazosin (I) is a representative of a group of drugs that block .alpha..sub.1 adrenoceptors. .alpha..sub.1 Receptors are innervated by postganglionic sympathetic neuronal fibers and are located in many body systems, including the cardiovascular system and the urinary tract. Evidence is now beginning to accumulate that there are subtypes of .alpha..sub.1 receptors, making .alpha..sub.1 adrenergic receptors a family of recognition units rather than a monolithic element. Bylund [FASEB J. 6, 832-839 (1992)] has presented evidence that there are at least three presently differentiable .alpha..sub.1 receptor subtypes. Prazosin (II), an achiral analog of doxazosin, is reported to have similar affinities for each of these subtypes. ##STR1## Doxazosin has a single chiral center located on the carbon adjacent to the carboxyl group (shown in formula I). This gives rise to a pair of enantiomers which have been resolved by Ley et al. [Recent Advances in Chiral Separations, Steven and Wilson Editors, Plenum Press, New York (1991) pages 97-103] on an analytical scale (0.52 .mu.g), but there are no reports in the literature of a preparative-scale separation of the enantiomers.
Although the inventor does not wish to be bound by a theoretical construct, it is possible that the beneficial effects of (+) doxazosin in increasing urine flow and bladder evacuation and in improving serum lipid profiles with minimal effects on such other cardiovascular parameters as blood pressure and heart rate arise from the selective inhibition of a specific subset of .alpha..sub.1 receptors by the (+) isomer as compared to its enantiomer, which may preferentially inhibit those subsets involved in regulating blood pressure.
The racemic mixture of doxazosin is presently used primarily as an antihypertensive agent. Doxazosin's oral bioavailability is good and the plasma half life in man is approximately 10 hours following both oral and intravenous administration. There are reports that the administration of racemic doxazosin leads to modestly decreased total cholesterol and LDL levels. [Young & Brogden Drugs 35, 525-541 (1988) and references therein.] There is also a report of the use of prazosin (II) to treat BPH [Hedlund et al., J. Urology 130, 275-278 (1983)]. However, neither of the drugs has enjoyed widespread use for either BPH or improvement of serum lipid profiles because of the cardiovascular effects that are the primary result of their administration.
A troublesome cardiovascular problem related to the use of previously known .alpha..sub.1 receptor antagonists for the treatment of BPH and the improvement of serum lipid profiles is their hypotensive activity, which is particularly reflected in the problem of orthostatic hypotension. Symptomatic orthostatic hypotension is most likely to occur with high initial doses of earlier .alpha..sub.1 antagonists or may occur when the dose is increased rapidly. A modest degree of fluid retention, which is another result of vasodilation, may be observed. Reflex tachycardia is also occasionally observed.
Many of the .alpha..sub.1 antagonists cause somewhat similar adverse effects. The incidence of reported side effects associated with racemic doxazosin-treated patients has varied among studies. The incidence of total side effects associated with doxazosin in patients treated for hypertension has ranged between 0 and 75%, but has generally been similar to that seen with other .alpha..sub.1 -blocking agents at dosages producing a similar reduction in blood pressure. The most frequently reported side effects have been postural hypotension, nausea, lethargy, fatigue and dizziness.
It would be particularly desirable to find an .alpha..sub.1 antagonist that exhibited the beneficial effect on serum lipids hinted at by the racemic mixture of doxazosin but which would not have effects on blood pressure and heart rate. It would also be desirable to find a superior and selective .alpha..sub.1 antagonist for the treatment of BPH.